TMB Dataset and Blood TMB Correlation With Tissue TMB eFigure 5. of Tumor Response Amongst Patients With PD-L1 TC 25% eTable 8. Baseline Demographics and Disease Characteristics (Patients With Blood TMB 20 and 20 mut/Mb) eTable 9. Baseline Demographics and Disease Characteristics (Patients With Tissue TMB 10 and 10 mut/Mb) eTable 10. Exploratory Analysis of Tumor Response Among Patients With Blood TMB 20 mut/Mb and 20 mut/Mb eTable 11. Safety Summary in Patients With PD-L1 TC 25% eTable 12. Safety Summary in Patients With Blood TMB 20 mut/Mb eTable 13. All-cause Adverse Events eTable 14. Treatment-related Serious Adverse Events Occurring in 2 Patients in Any Treatment Group eTable 15. Treatment-related Adverse Events Leading to Treatment Discontinuation Occurring in 2 Patients Vicagrel in Any Treatment Group eTable16. Immune-mediated Adverse Events (Grouped Terms) Occurring in 2 Patients in Any Treatment Group eReferences. jamaoncol-6-661-s001.pdf (1.1M) GUID:?1B57960F-15D4-47F3-A3BF-D58A4DA2487B Supplement 2: Trial Protocol. jamaoncol-6-661-s002.pdf (14M) GUID:?C6DCEAF4-D540-4D7C-B6E4-C2FF81ED2001 Supplement 3: Data Sharing Statement. jamaoncol-6-661-s003.pdf (125K) GUID:?332161EB-003E-4395-A25F-F7EC247A4255 Key Points Question Does first-line durvalumab treatment with or without tremelimumab improve survival outcomes vs chemotherapy in patients with metastatic nonCsmall cell lung cancer? Findings In this phase 3 randomized clinical trial including 1118 patients with nonCsmall cell lung cancer, although the trial did not meet its primary end points, treatment with durvalumab resulted in a numerically reduced risk of death vs chemotherapy in patients with programmed cell death ligand 1 expression on at least 25% of tumor cells. In exploratory analyses, a blood tumor mutational burden threshold of at least 20 mutations per megabase was identified for optimal clinical benefit with durvalumab plus tremelimumab vs chemotherapy. Meaning These findings highlight the need for further investigation and prospective validation of blood tumor mutational burden as a predictive biomarker for immunotherapy. Abstract Importance Checkpoint inhibitors targeting programmed cell death Vicagrel 1 or its ligand (PD-L1) as monotherapies Vicagrel or in combination with antiCcytotoxic Vicagrel T-lymphocyteCassociated antigen 4 have shown clinical activity in patients with metastatic nonCsmall cell lung cancer. Objective To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic nonCsmall cell lung cancer. Design, Setting, and Participants This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic nonCsmall cell lung cancer who had no sensitizing or genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Vicagrel Data were collected from July 21, 2015, to October 30, 2018. Interventions Patients were randomized (1:1:1) to receive treatment with durvalumab ILF3 (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. Main Outcomes and Measures The primary end points, assessed in patients with 25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. Results Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with 25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; or genetic alterations and those with symptomatic, unstable brain metastases were excluded (eTable 1 in Supplement 1). The study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The protocol and all modifications (Supplement 2) were approved by the institutional review boards or ethics committees.